Abstract The US is in the midst of a major opioid epidemic largely attributed to synthetic opioids. For example, fentanyl is 50-100 times more potent than heroin and is involved in >60% of overdoses nationwide and >90% of overdoses in Ohio, although this is almost certainly an underestimate of recreational use. Individuals with opioid use disorder are at significant risk for transmission of HIV, and new cases of HIV are on the rise in the Midwest and at our institution. Opioid receptors are expressed in a variety of cell types that are susceptible to HIV infection. Commonly abused opioids promote HIV replication and virus-mediated pathology. Thus, translational research on virus-opioid interactions is essential for optimized treatment and limiting viral reactivation. Important knowledge regarding how synthetic opioids influence HIV latency and reactivation is absent from the available literature. To fill this critical gap and institute a major shift forward in our understanding of this epidemic, we propose a series of complementary in vivo studies to directly evaluate the impact of synthetic opioids on markers of HIV latency/reactivation, viral diversity, transcription factor expression, microRNA expression, and cell signaling pathways.